Cytomegalovirus (CMV) is a leading infectious complication in transplant recipients and may cause mild or severe clinical manifestations. In addition, circumstantial evidence has linked CMV infection to allograft' rejection. The immune mechanisms contributing to this range of CMV disease outcomes are unknown. CMV-specific cell-mediated immunity is not only crucial for the control of viral replication and protection from severe disease, but may also contribute to immune-mediated rejection of transplanted organs. Factors contributing to the balance between protective and pathologic CMV-specific CD8+ T cell responses have not been fully described and may influence the outcome of CMV infection. Previous work has suggested that broad specificity and lytic function may be important for immune protection, while cross-reactive T cells specific for virus and alloantigens may contribute to allograft rejection. The proposed studies will therefore test the overall hypothesis that primary CMV infection in renal transplant recipients generates CMV-specific CD8+ T cell responses that not only protect the host by controlling viral replication and limiting the severity of disease manifestations, but also increase the risk of allograft rejection by generating CMV-specific CD8+ T cells that cross-react with alloantigens. The goals of the proposed studies are 1) to determine patterns of CMV-specific CD8+ T cell antigen recognition and/or anti-viral effector function that confer protective immunity during and after resolution of primary CMV infection, and 2) to determine whether cross-reactive CMV epitope- and alloantigen-specific CD8+ T cells are generated during primary CMV infection, and if so, how these cells impact overall anti-viral and alloreactive CD8+ T cell responses. Initial experiments will examine CMV protein-specific CD8+ T cell responses against several gene products, and fine epitope mapping studies will allow the synthesis of MHC class l-peptide tetramer complexes to identify CMV epitope-specific CD8+ T cells. These reagents will then be used to characterize patterns of antigen recognition and functional properties of CMV epitope-specific CD8+ T cells and to correlate these findings with disease outcome (peripheral blood CMV load and severity of CMV disease). Tetramers will also be used to identify cross-reactive CD8+ T cells that may be generated following primary CMV infection and compare them to the overall anti-CMV and alloreactive CD8+ T cell responses. These studies will contribute new knowledge to aid in the rational development of effective CMV prevention and treatment strategies for populations at risk for severe CMV disease.